This study reports the synthesis of a series of 2-aroylisoindoline hydroxamic acids employing N-benzyl, long alkyl chain and acrylamide units as diverse linkers. In-vitro studies led to the identification of N-benzyl linker-bearing compound (10) and long chain linker-containing compound (17) as dual selective HDAC6/HSP90 inhibitors. Compound 17 displays potent inhibition of HDAC6 isoform (IC50 = 4.3 nM) and HSP90a inhibition (IC50 = 46.8 nM) along with substantial cell growth inhibitory effects with GI50 = 0.76 μM (lung A549) and GI50 = 0.52 μM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI50 = 0.37 μM) and lung H1975 cell lines (GI50 = 0.13 μM) mediated through selective HDAC6 inhibition (IC50 = 33.3 nM) and HSP90 inhibition (IC50 = 66 nM). In addition, compound 17 also modulated the expression of signatory biomarkers associated with HDAC6 and HSP90 inhibition. In the in vivo efficacy evaluation in human H1975 xenografts, 17 induced slightly remarkable suppression of tumor growth both in monotherapy as well as the combination therapy with afatinib (20 mg/kg). Moreover, compound 17 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner suggesting that dual inhibition of HDAC6 and HSP90 can modulate immunosuppressive ability of tumor area.

中文翻译：

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基于异吲哚啉支架的HDAC6和HSP90双重抑制剂在体外和体内抑制肺癌的生长。

这项研究报告了一系列使用N-苄基，长烷基链和丙烯酰胺单元作为不同接头的2-芳基异吲哚啉异羟肟酸的合成方法。体外研究导致鉴定出具有N-苄基接头的化合物（10）和含长链接头的化合物（17）作为双重选择性HDAC6 / HSP90抑制剂。化合物17表现出对HDAC6同工型（IC50 = 4.3 nM）和HSP90a抑制作用（IC50 = 46.8 nM）的有效抑制作用，以及对GI50 = 0.76μM（肺A549）和GI50 = 0.52μM（对EGFR耐药的H1975肺结核）的细胞生长抑制作用。化合物10显示出对肺A549（GI50 = 0.37μM）和肺H1975细胞系（GI50 = 0.13μM）的有效抗增殖活性，该细胞系通过选择性HDAC6抑制（IC50 = 33.3 nM）和HSP90抑制（IC50 = 66 nM）介导。此外，化合物17还调节与HDAC6和HSP90抑制有关的标志性生物标志物的表达。在人类H1975异种移植物中的体内功效评估中，有17种在单药治疗以及与阿法替尼（20 mg / kg）的联合治疗中均诱导了肿瘤生长的轻微显着抑制。此外，化合物17可以剂量依赖性方式有效降低IFN-γ处理的肺H1975细胞中程序性死亡配体1（PD-L1）的表达，这表明HDAC6和HSP90的双重抑制可以调节肿瘤区域的免疫抑制能力。